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NFKB modulation
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Research News:
Pharmaceutical companies are currently scrambling to develop
clinically useful synthetic inhibitors of NF-kappaB. These companies will
eventually be successful in this endeavor, and we can also confidently predict
that the pharmaceutical version of NF-kappaB suppression will arrive with a
plethora of adverse effects, most likely because of the potency and specificity
of the drug. NF-kappaB plays an important role in a wide range of normal,
healthy physiologic processes, including the immune response to infectious
diseases. We should therefore seek to modulate its function rather than
sophomorically suppress its function. Fortunately, we can do this with several
natural interventions, not the least of which are vitamin D[1],[2], curcumin[3]
(requires piperine for absorption[4]), lipoic acid[5], green tea[6],
rosemary[7], grape seed extract[8], propolis[9], zinc[10], high-dose
selenium[11], indole-3-carbinol[12],[13], N-acetyl-L-cysteine[14], and
resveratrol.[15],[16] Other nutrients such as isohumulones from Humulus
lupulus[17] and fatty acids inhibit NF-kappaB indirectly via activation of
peroxisome proliferator-activated receptors alpha (PPAR-ά) and gamma (PPAR-γ).
GLA activates PPAR-gamma and thereby inhibits NF-kappaB[18], while (oxidized)
EPA activates PPAR-alpha and thus inhibits NF-kappaB[19]; these latter findings
reflect a quantum leap in our understanding of the mechanisms of diet-induced
anti-inflammation (i.e., anti-inflammatory nutrigenomics, or anti-inflammatory
immunonutrigenomics) since they show that food constituents modify human
physiology and phenotype at the genetic/pre-transcriptional level and not only
at the metabolic/post-transcriptional level as was previously thought.[20]
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[1] “1Alpha,25-dihydroxyvitamin D3 (1,25-(OH)2-D3), the active metabolite of
vitamin D, can inhibit NF-kappaB activity in human MRC-5 fibroblasts, targeting
DNA binding of NF-kappaB but not translocation of its subunits p50 and p65.”
Harant H, Wolff B, Lindley IJ. 1Alpha,25-dihydroxyvitamin D3 decreases DNA
binding of nuclear factor-kappaB in human fibroblasts. FEBS Lett. 1998 Oct
9;436(3):329-34
[2] “Thus, 1,25(OH)2D3 may negatively regulate IL-12 production by
downregulation of NF-kB activation and binding to the p40-kB sequence.”
D'Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di Lucia P, Lang R,
Sinigaglia F, Panina-Bordignon P. Inhibition of IL-12 production by
1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in
transcriptional repression of the p40 gene. J Clin Invest. 1998 Jan
1;101(1):252-62
[3] “Curcumin, EGCG and resveratrol have been shown to suppress activation of
NF-kappa B.” Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS.
Molecular mechanisms underlying chemopreventive activities of anti-inflammatory
phytochemicals: down-regulation of COX-2 and iNOS through suppression of
NF-kappa B activation. Mutat Res. 2001 Sep 1;480-481:243-68
[4] Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of
piperine on the pharmacokinetics of curcumin in animals and human volunteers.
Planta Med. 1998 May;64(4):353-6
[5] “ALA reduced the TNF-alpha-stimulated ICAM-1 expression in a dose-dependent
manner, to levels observed in unstimulated cells. Alpha-lipoic acid also reduced
NF-kappaB activity in these cells in a dose-dependent manner.” Lee HA, Hughes
DA.Alpha-lipoic acid modulates NF-kappaB activity in human monocytic cells by
direct interaction with DNA. Exp Gerontol. 2002 Jan-Mar;37(2-3):401-10
[6] “In conclusion, EGCG is an effective inhibitor of IKK activity. This may
explain, at least in part, some of the reported anti-inflammatory and anticancer
effects of green tea.” Yang F, Oz HS, Barve S, de Villiers WJ, McClain CJ,
Varilek GW. The green tea polyphenol (-)-epigallocatechin-3-gallate blocks
nuclear factor-kappa B activation by inhibiting I kappa B kinase activity in the
intestinal epithelial cell line IEC-6. Mol Pharmacol. 2001 Sep;60(3):528-33
[7] “These results suggest that carnosol suppresses the NO production and iNOS
gene expression by inhibiting NF-kappaB activation, and provide possible
mechanisms for its anti-inflammatory and chemopreventive action.” Lo AH, Liang
YC, Lin-Shiau SY, Ho CT, Lin JK. Carnosol, an antioxidant in rosemary,
suppresses inducible nitric oxide synthase through down-regulating nuclear
factor-kappaB in mouse macrophages. Carcinogenesis. 2002 Jun;23(6):983-91
[8] “Constitutive and TNFalpha-induced NF-kappaB DNA binding activity was
inhibited by GSE at doses > or =50 microg/ml and treatments for > or =12 h.”
Dhanalakshmi S, Agarwal R, Agarwal C. Inhibition of NF-kappaB pathway in grape
seed extract-induced apoptotic death of human prostate carcinoma DU145 cells.
Int J Oncol. 2003 Sep;23(3):721-7
[9] “Caffeic acid phenethyl ester (CAPE) is an anti-inflammatory component of
propolis (honeybee resin). CAPE is reportedly a specific inhibitor of nuclear
factor-kappaB (NF-kappaB).” Fitzpatrick LR, Wang J, Le T. Caffeic acid phenethyl
ester, an inhibitor of nuclear factor-kappaB, attenuates bacterial peptidoglycan
polysaccharide-induced colitis in rats. J Pharmacol Exp Ther. 2001
Dec;299(3):915-20
[10] "Our results suggest that zinc supplementation may lead to downregulation
of the inflammatory cytokines through upregulation of the negative feedback loop
A20 to inhibit induced NF-kappaB activation." Prasad AS, Bao B, Beck FW, Kucuk
O, Sarkar FH. Antioxidant effect of zinc in humans. Free Radic Biol Med. 2004
Oct 15;37(8):1182-90
[11] Note that the patients in this study received a very high dose of selenium:
960 micrograms per day. This is at the top—and some would say over the top—of
the safe and reasonable dose for long-term supplementation. In this case, th
study lasted for three months. "In patients receiving selenium supplementation,
selenium NF-kappaB activity was significantly reduced, reaching the same level
as the nondiabetic control group. CONCLUSION: In type 2 diabetic patients,
activation of NF-kappaB measured in peripheral blood monocytes can be reduced by
selenium supplementation, confirming its importance in the prevention of
cardiovascular diseases." Faure P, Ramon O, Favier A, Halimi S. Selenium
supplementation decreases nuclear factor-kappa B activity in peripheral blood
mononuclear cells from type 2 diabetic patients. Eur J Clin Invest. 2004
Jul;34(7):475-81
[12] Takada Y, Andreeff M, Aggarwal BB. Indole-3-carbinol suppresses NF-{kappa}B
and I{kappa}B{alpha} kinase activation causing inhibition of expression of NF-{kappa}B-regulated
antiapoptotic and metastatic gene products and enhancement of apoptosis in
myeloid and leukemia cells. Blood. 2005 Apr 5; [Epub ahead of print]
[13] "Overall, our results indicated that indole-3-carbinol inhibits NF-kappaB
and NF-kappaB-regulated gene expression and that this mechanism may provide the
molecular basis for its ability to suppress tumorigenesis." Takada Y, Andreeff
M, Aggarwal BB. Indole-3-carbinol suppresses NF-kappaB and IkappaBalpha kinase
activation, causing inhibition of expression of NF-kappaB-regulated
antiapoptotic and metastatic gene products and enhancement of apoptosis in
myeloid and leukemia cells. Blood. 2005 Jul 15;106(2):641-9. Epub 2005 Apr 5.
[14] "CONCLUSIONS: Administration of N-acetylcysteine results in decreased
nuclear factor-kappa B activation in patients with sepsis, associated with
decreases in interleukin-8 but not interleukin-6 or soluble intercellular
adhesion molecule-1. These pilot data suggest that antioxidant therapy with N-acetylcysteine
may be useful in blunting the inflammatory response to sepsis." Paterson RL,
Galley HF, Webster NR. The effect of N-acetylcysteine on nuclear factor-kappa B
activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1
expression in patients with sepsis. Crit Care Med. 2003 Nov;31(11):2574-8
[15] “Resveratrol's anticarcinogenic, anti-inflammatory, and growth-modulatory
effects may thus be partially ascribed to the inhibition of activation of NF-kappaB
and AP-1 and the associated kinases.” Manna SK, Mukhopadhyay A, Aggarwal BB.
Resveratrol suppresses TNF-induced activation of nuclear transcription factors
NF-kappa B, activator protein-1, and apoptosis: potential role of reactive
oxygen intermediates and lipid peroxidation. J Immunol. 2000 Jun
15;164(12):6509-19
[16] “Both resveratrol and quercetin inhibited NF-kappaB-, AP-1- and CREB-dependent
transcription to a greater extent than the glucocorticosteroid, dexamethasone.”
Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung RH, Ito K, Russell RE,
Barnes PJ.Anti-inflammatory Effects of Resveratrol in Lung Epithelial Cells:
Molecular Mechanisms. Am J Physiol Lung Cell Mol Physiol. 2004 Jun 4 [Epub ahead
of print]
[17] Yajima H, Ikeshima E, Shiraki M, Kanaya T, Fujiwara D, Odai H,
Tsuboyama-Kasaoka N, Ezaki O, Oikawa S, Kondo K. Isohumulones, bitter acids
derived from hops, activate both peroxisome proliferator-activated receptor
alpha and gamma and reduce insulin resistance. J Biol Chem. 2004 Aug
6;279(32):33456-62. Epub 2004 Jun 3.
http://www.jbc.org/cgi/content/full/279/32/33456
[18] “Thus, PPAR gamma serves as the receptor for GLA in the regulation of gene
expression in breast cancer cells. “ Jiang WG, Redfern A, Bryce RP, Mansel RE.
Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the
action of gamma linolenic acid in breast cancer cells. Prostaglandins Leukot
Essent Fatty Acids. 2000 Feb;62(2):119-27
[19] "...EPA requires PPARalpha for its inhibitory effects on NF-kappaB." Mishra
A, Chaudhary A, Sethi S. Oxidized omega-3 fatty acids inhibit NF-kappaB
activation via a PPARalpha-dependent pathway. Arterioscler Thromb Vasc Biol.
2004 Sep;24(9):1621-7. Epub 2004 Jul 1.
http://atvb.ahajournals.org/cgi/content/full/24/9/1621
[20] “Indeed, the previous view that nutrients only interact with human
physiology at the metabolic/post-transcriptional level must be updated in light
of current research showing that nutrients can, in fact, modify human physiology
and phenotype at the genetic/pre-transcriptional level.” Vasquez A. Reducing
pain and inflammation naturally - part 4: nutritional and botanical inhibition
of NF-kappaB, the major intracellular amplifier of the inflammatory cascade. A
practical clinical strategy exemplifying anti-inflammatory nutrigenomics.
Nutritional Perspectives, July 2005:5-12. www.OptimalHealthResearch.com/part4
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Dr Vasquez's Comments:
This is an excerpt from my textbook "Chiropractic and Naturopathic
Mastery of Common Clinical Disorders" which is available from
OptimalHealthResearch.com
(website with clinical information designed for doctors) and also from
OptimalHealthNutrition.com
in our selection of books.
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